Calixarenes and their use for sequestration of metals

ABSTRACT

Disclosed are “acid-amide” calixarenes of formula (I) wherein: L is [—CH 2 —] or [—O—CH 2 —O—] and may be the same or different between each aryl group R 5  is H, halogen, or C 1-C   10  aliphatic hydrocarbyl group, C 6-C   20  aryl group, any of which may optionally be substituted by one or more halo or oxo groups or interrupted by one or more oxo groups, and R 5  may be the same or different on each aryl group; R 1  comprises an optionally protected carboxy group; two groups out of R 2 , R 3 , and R 4 , are H; the one group out of R 2 , R 3 , and R 4  not being H comprises an amide group. The amide group may be linked to a second calixarene to form a dimer. Also disclosed are methods of use of such calixarenes for the purposes of metal sequestration, especially of lanthanides and actinides. Also disclosed are calixarene dimer derivatives of the calixarenes of the invention. Also disclosed are processes for preparing the calixarenes and dimers

This application is a division of application Ser. No. 09/460,237, filedDec. 13, 1999, now U.S. Pat. No. 6,297,395 which is a cip of Ser. No.09/068,148, filed Oct. 14, 1998 ABN the entire content of which ishereby incorporated by reference in this application.

The present invention relates to novel calixarenes, methods of theirpreparation, and uses thereof, in particular for the sequestration ofmetals.

European Patent Publication No. 0 432 989 describes a number ofcalixarene and oxacalixarene derivatives as having metal sequesteringproperties, and reviews some of the prior art in this field.

In a first aspect of the present invention there is disclosedcalixarenes of the formula (I). The term calixarenes as used hereinafteris intended to embrace also oxacalixarenes,

wherein:

L is [C—CH₂—] or [—O—CH₂—O—] and may be the same or different betweeneach aryl group.

R⁵ is H, halogen, or C₁-C₁₀ aliphatic hydrocarbyl group, C₆-C₂₀ arylgroup, C₆-C₂₀ hydrocarbylaryl group, any of which may optionally besubstituted by one or more halo or oxo groups or interrupted by one ormore oxo groups, and R⁵ may be the same or different on each aryl group.

R¹ comprises a carboxy group [—COO⁻] which may or may not be protonatedor protected. Suitable protecting derivatives include salts and esterderivatives of the carboxylic acid.

two groups out of R², R³, and R⁴ are H

the one group out of R², R³, and R⁴ not being H comprises an amide.group

The combination of ‘acid’ (or protected acid) and ‘amide’ in thecalixarenes of the present invention is not found in the calixarenes ofthe prior art; this combination leads to unexpected and desirable metalsequestering properties (particularly for lanthanide and actinidecations) as will be further discussed below.

Preferably:

R² and R⁴ are H and R³ comprises the amide group; L is [—CH₂—]— betweeneach of the aryl groups;

R⁵ is tertiary alkyl, especially butyl.

Preferably the carboxy group R¹ conforms to the general formula (A):

[—X—COOR¹⁰]  (A)

wherein X is a C₁, a C₂ or a C₃ carbon chain being a part of analiphatic hydrocarbyl group, aryl group or hydrocarbylaryl group, any ofwhich may optionally be substituted by one or more halo, oxo or nitrogroups.

R¹⁰ is H or a protecting group being a salt or an Ester derivative.Salts include metal salts e.g. alkali (such as Li) or alkali earthmetals, or ammonium or substituted ammonium derivatives. The choice ofsalt should be made such as to prevent the cation interfering with theoperation of the calixarene in practice. Ester groups may be formed withC₁-C₁₀ aliphatic alkyl alcohols, C₆-C₂₀ aryl alcohols, C₆-C₂₀hydrocarbylaryl alcohols, any of which may optionally be substituted byone or more halo, nitro, or oxo groups or interrupted by one or more oxogroups. Examples include benzyl, p-methoxybenzyl, benzoylmethyl,p-nitrobenzyl, methyl, ethyl, butyl, t-butyl etc.

More preferably R¹ is of the general formula (B):

[—(C.R⁶.R⁷)_(a)—COOR¹⁰]  (B)

wherein n is 1, 2 or 3 and R⁶ and R⁷ are H or halogen and can be thesame or different on each carbon.

Alternatively R¹ may be of the general formula (C):

wherein n is 0 or 1 and R⁶ and R⁷ are H or halogen and can be the sameor different on each carbon and wherein the phenyl ring of the benzoicacid group may be optionally substituted by one or more halo, oxo ornitro groups.

In each case it is preferable that a is 1 and R⁶, R⁷ and R¹⁰ are all H.

In unprotected acid embodiments, preferably the aliphatic hydrocarbylgroup, aryl group or hydrocarbylaryl group of X in formula (A) aresubstituted by one or more groups which cause a reduction in the pKa ofthe carboxy group with respect to the unsubstituted molecule e.g. nitro.

For instance the phenyl ring of the benzoic acid of formula (C) ispreferably substituted by one or more groups which cause a reduction inthe pKa of the carboxy group with respect to the unsubstituted moleculee.g. nitro.

Preferably the amide group R², R³, or R⁴ of formula (I) is of thegeneral formula (D):

wherein n is 1, 2 or 3 and R⁶ and R⁷ are H, halogen, or C₁-C₁₀ aliphatichydrocarbyl group, and can be the same or different on each carbon, andwherein R⁸ and R^(9,) which may be the same or different, are H orC₁-C₁₀ aliphatic hydrocarbyl group (optionally halo substituted)including a cycloaliphatic ring formed by R⁸ and R⁹ together.

In certain embodiments of the invention, as described in more detailbelow, R⁸ or R⁹ may form a bridge to between a calixarene of the presentinvestigation and a further calixarene in order to produce a dimer.

Most preferably, the calixarene is of the formula (II):

(5,11,17,23-tetra-tert-butyl-25-[hydroxycarbomylmethoxy]-27-[(N-diethylamino)carbomylmethoxy]-26-28-dihydroxy-calix[4]arene.)

This compound (“acid-amide”) has been found to be useful for theextraction of both divalent and trivalent metal ions such as Pb, Sr, Hg,Bi and Y; in particular Lanthanides (e.g. La) and Actinides (e.g. U).

Also embraced by the present invention are calixarenes of the generalformulae (I) and (II) but wherein some or all of phenyl groups of thecalixarene ring are further peripherally substituted in such a way asnot to compromise the advantageous combination of the carboxy and amidegroups which form the central core of the present invention. Possiblesubstituents include halogen, nitro, C₁-C₁₀ aliphatic hydrocarbyl group,C₆-C₂₀ aryl group, or C₆-C₂₀ hydrocarbylaryl group, any of which mayoptionally be substituted by one or more halo or oxo groups orinterrupted by one or more oxo groups. Indeed certain substituents (e.g.nitro) may be desirable in as much as they reduce the pKa values of thetwo hydroxy groups of the calixarene ring, thereby modifying themetal-chelating properties of the compound.

In a second aspect of the present invention there is disclosed a methodof sequestering metals comprising contacting the metals with acalixarene as described above.

Preferably the calixarene is used to complex metals at a pH of 2-6,(most preferably pH 3-6) since at higher pHs there is an increased riskof the target metal precipitating. For instance, precipitation ofLanthanides occurs at fairly low pH (7.5 for La, 6.4 for Lu).

If required, additional complexing agents (such as are well known to theskilled person) may be used to prevent precipitation of target metals.This allows the use of the calixarene at higher pHs, which willadvantageously reduce protonation of the carboxy and hydroxy groups. Theuse of such additional complexing agents can thus raise the usefulworking pH range of the calixarene to the point at which themetal-calixarene complex itself an precipitates e.g. around pH 11.

The use of higher pHs (e.g. pH 7 to 10, preferably pH 9) may beparticularly advantageous for increasing the concentration of negativecharge in calixarenes having protected acid groups or incalixarene-dimers, which may otherwise be reduced by the protectinggroup or steric effects respectively.

If desired the environmental pH may be adjusted using conventionalmethods of the art. For instance if it is desired to raise the pH, thenLiOH may be added. If desired, the pH may be buffered by using anappropriate buffer such as are well known to those skilled in this arteg. citrate.

In all cases the lower pH limit of useful operation will be dependent onthe pKa of each chelating group in the calixarene, since that willdictate whether each (unprotected) carboxy or hydroxy group will beprotonated at any given pH. It may therefore be desirable for each groupto have a low pKa e.g. when treating acidic waste streams for which thepH cannot be readily adjusted. The pKa of the protonated carboxy and theamide group of the calixarene of formula (II) is less than 3.

Preferably the calixarene is dissolved in a hydrophobic organic solvent(e.g. dichloromethane) and this is mixed with an aqueous phasecontaining metal ions (e.g. in equal volumes).

The phases are then stirred or otherwise agitated, typically for around1 hour, followed by a 2 hour separation time.

Preferably the calixarene is present in excess over the metal targete.g. 25-fold, or 250-fold. The excess required for useful extractionwill depend on the nature of the metal target e.g. size, charge etc.

Preferably the metal target is U, Hg, Am, Pb, Sr, Bi, or Y for instancein methods of environmental clean up. Alternatively the metal could bean actinide such as Am or another lanthanide.

The calixarenes described above are such that the metal complexes formedwith the target ion may be overall neutral without the necessity foradditional counter-anions. A further advantage is that the calixarenescan be highly selective, thereby preventing unwanted metal ionscomplexing all available sites.

A still further advantage of the methods of the current invention isthat the extracted metal ions can be recovered following sequestrationinto the hydrophobic phase simply by contacting that phase with arelatively small (with respect to the original metal-containing sample)volume of acid (e.g. 1 M) thereby causing the pH to drop and the metalto become decomplexed and enter the acid aqueous phase. The calixarenecan then be reused simply by evaporation of the solvent.

Alternatively, the extracted metal ions can be recovered followingextraction simply by evaporating the solvent to leave themetal-calixarene complex.

Thus in preferred forms, e.g. using the ‘acid-amide’ above, theextraction methods of the present invention are both selective andefficient and do not require additional ions to operate. The nature ofthe extraction can be readily optimised by adjustment of the pH.

In a third aspect of the invention there is disclosed a solidphase-bound calixarene of the type described above e.g. polymer bound.For instance the calixarene may be physisorbed and immobilised ontopolystyrene divinyl benzene beads. Immobilisation of the calixarene on asolid phase support may assist in the extraction methods of theinvention. The preparation of such bound calixarenes would present noundue burden to those skilled in the art, in the light of the presentdisclosure in conjunction with the methods, or methods analogous to themethods, described by Harris et al. in U.S. Pat. No. 4,642,362 or4,699,966, or Parker in U.S. Pat. No. 4,447,585 or Tetrahedron 36461-510 (1980), or in European Patent Publication No. 0 217 656.

In a fourth aspect of the invention there is disclosed a process forpreparing the calixarenes described above. Intermediates for use in theprocess form a fifth aspect of the invention.

In a sixth aspect of the invention there is disclosed a calixarene dimercomprising two calixarenes of formula (I) wherein the amide group ofeach is of the general formula (D) above, and wherein the R⁸ or R⁹ groupof one calixarene is conjugated to the R⁸ or R⁹ of the other calixarene,optionally through a spacer group R¹¹ as shown schematically in formula(III):

The optional spacer group R¹¹ may be C₁-C₆ aliphatic hydrocarbyl group,C₆-C₁₀ aryl group, C₆-C₁₆ hydrocarbylaryl group, any of which mayoptionally be substituted by one or more halo or oxo groups orinterrupted by one or more oxo groups. In the absence of a spacer groupthe R⁸ or R⁹ group of one calixarene is conjugated directly to the R⁸ orR⁹ group of the other. In any case it is preferable that there is only1, 2, 3 or 4 bridging atoms (preferably carbon atoms) between theNitrogen atoms of the two amide groups. Most preferably there is 2 or 3bridging carbon atoms. As described in more detail below, this spacingbetween the calixarenes may help to pre-stress the dimer into aparticular stable, low-energy, chelating conformation, and therebyenhancing the specificity for target metals with respect to calixarenemonomers. groups or interrupted by one or more oxo groups. In theabsence of a spacer group the R⁸ or R⁹ group of one calixarene isconjugated directly to the R⁸ or R⁹ group of the other. In any case itis preferable that there is only 1, 2, 3 or 4 bridging atoms (preferablycarbon atoms) between the Nitrogen atoms of the two amide groups. Mostpreferably there is 2 or 3 bridging carbon atoms. As described in moredetail below, this spacing between the calixarenes may help topre-stress the dimer into a particular stable, low energy, chelatingconformation, and thereby enhancing the specificity for target metalswith respect to calixarene monomers.

In a further aspect of the invention there is disclosed a calixarene offormula (IV):

wherein:

L is [—CH₂—] or [—O—CH₂O—] and is the same or different between eacharyl group; R⁵ is halogen, or is a C₁-C₁₀ aliphatic hydrocarbyl group,C₆-C₂₀ aryl group or a C₆-C₂₀ hydrocarbylaryl group, any of which isoptionally substituted by one or more halo or oxo or is interrupted byone or more oxo groups, and R⁵ is the same or different on each arylgroup;

R¹ is a carboxy group which is or is not protonated or protected; twogroups out of R², R³ and R⁴ are H; and

the one group out of R², R³ and R⁴ which is not H is a thioamide group.

In a preferred embodiment R² and R⁴ are H, R⁵ is the same on each arylgroup and is a

Alternatively, R² and R⁴ are H, R⁵ is the same on each aryl group and isa tertiary

In another embodiment of the invention there is disclosed a method forpreparing the calixarenes of formula (IV) above.

Furthermore, there is described a method for the sequestration of metalscomprising contacting the metals with a calixarene of formula (IV) asdescribed above.

The compounds, methods and processes of the present invention will nowbe described, by way of illustration only, through reference to thefollowing Figures ad Examples. Other embodiments falling within thescope of the invention will occur to those skilled in the art in thelight of these.

FIGURES

FIG. 1 shows the acid-amide of the present invention.

FIG. 2 shows the efficiency of extraction of La (III) by acid-amide as afunction of concentration ratio of the two.

FIG. 3 shows the efficiency of extraction of La (III) by acid-amide as afunction of the presence of various anions (citrate, acetate, picrate).

FIG. 4 shows the efficiency of extraction of La (III) by acid-amide as afunction of concentration of buffer (citrate).

FIG. 5 shows the efficiency of competitive extraction of differentLanthanide (III) cations by acid-amide in the presence of buffer(citrate).

FIG. 6 shows the efficiency of extraction of various metals byacid-amide in the presence of buffer (citrate).

FIG. 7 shows the efficiency of extraction of various metals byacid-amide in the absence of buffer.

FIG. 8 shows the structure of an acid-amide/Ln (III) complex, asdetermined by X-ray crystallography.

FIG. 9 shows the structure of an acid-amide/Lu (III) complex, asdetermined by X-ray crystallography.

FIG. 10 shows a calixarene dimer (designated 13b) according to thepresent invention.

FIG. 11 shows a calixarene dimer (designated 11b) according to thepresent invention, having an aryl spacer group between the Nitrogenatoms of the two amide groups.

FIG. 12 shows a calixarene dimer (designated 10) according to thepresent invention wherein the carboxy groups of the calixarenes havebeen protected by esterification with benzyl alcohol. The Nitrogen atomsof the two amide groups are linked via a 2-C ethyl bridge. The tertiarygroup of the Nitrogens (designated R⁹) is methyl in each case.

FIG. 13 shows a calixarene dimer (designated 11) according to thepresent invention wherein the carboxy groups of the calixarenes havebeen protected by esterification with benzyl alcohol. The Nitrogen atomsof the two amide groups are linked via a 2-C ethyl bridge. The tertiarygroup of the Nitrogens (designated R⁹) is hydrogen in each case.

FIG. 14 shows a calixarene dimer (designated 11a) according to thepresent invention, wherein the carboxy groups of the calixarenes havebeen protected by as an ethyl ester. The Nitrogen atoms of the two amidegroups are linked via a 3-C aromatic bridge. The tertiary group of theNitrogens is hydrogen in each case.

FIG. 15 shows a synthetic scheme for the acid-amide (954)

FIG. 16 shows a synthetic scheme for the azacrown-acid calix[4]arenesA957 and A959.

FIG. 17 shows a synthetic route for the ester-thioamide A960 and theacid-thioamide A961.

FIG. 18 shows the variation in % extraction of Cadmium (Cd) ions withthe molar ratio of Calixarene:Cd for acid-amide A954, ester-thioamideA960 and acid-thioamide A961 at pH=9.4.

EXAMPLES Example 1

The pH changes associated with the combination of various of the agentsused in the later examples was first measured in order to betterinterpret the findings. The standard extraction of dichloromethane andaqueous phase in equal volumes with 1 hour stirring plus 2 hoursseparation was employed. The La (III) was used at a concentration of 0.4mM, and the other agents were used in a ratio of 1:3:24 for La(III):citrate:acid-amide. The results, measured to +/−0.1 pH units, areshown in Table 1.

TABLE 1 Solution pH before pH after type extraction extraction (noagents) 5.6 5.5 acid-amide 5.6 5.6 La (III) 5.6 4.9 acid-amide La (III)5.6 4.9 Citrate 6.0 6.1 Citrate acid-amide 6.0 6.1 Citrate La (III) 6.06.0 Citrate acid-amide 6.0 6.1 La (III)

Example 2

The efficiency of extraction of La (III) by acid-amide as a function ofthe concentration ratio of the two was measured at an initial pH of 5.8(FIG. 2). The pH was not maintained at this level during the experiment.A result of 90% extraction was achieved using a large (250 x) excess ofacid-amide. It is postulated that this large excess was required becauseof a drop in pH during the course of the experiment (see Example 1)which led to reduced deprotonation of the three ionizable groups. In asimilar experiment using UO₂ ²+ only a 25 x excess was required,possibly because as a divalant cation it can still be efficiently boundwhen the three ionizable groups of the acid-amide are partiallyprotonated.

Example 3

The effect of various anions on the efficiency of extraction is shown inFIG. 3. Citrate was found to be the best, probably because of itsbuffering ability. In order to demonstrate that citrate is not itselfinvolved in the actual extraction or complexation of La (III), LiOH wastitrated into the mixture to retain pH 6 instead of using a citratebuffer. The level of extraction obtained (90% La (III)) was similar tothat achieved with citrate, indicating that citrate is not actuallyrequired to achieve efficient acid-amide extraction. The postulatednon-coordination of the La (III) by citrate when acid-amide is presentindicates a high formation constant (i.e. tight binding) for the La(III)/acid-amide complex.

Example 4

The optimum amount of citrate required for La (III) extraction wasassessed (FIG. 4). The results indicate that a 3x excess over La (III)is suitable.

Example 5

The efficiency of competitive extraction of various members of theLanthanide series is shown in FIG. 5. The efficiency appears to drop offacross the series, probably as a result of the change in the size of themetal cations. The results with Lanthanides indicate that it is likelycertain actinides such as Am (III) will also be efficiently extracted.

Example 6

The efficiency of extraction of various metals by acid-amide in thepresence of citrate was measured, the results being shown in FIG. 6. Theresults indicate high selectivity within the broad range of elementsassessed. The extraction of La, U, Hg, Sr, Eu, Tm, Lu, Bi, and Pb isespecially efficient, particularly as compared with the alkali and thesmaller alkali-earth metals, and various other transition metals.

Example 7

FIG. 7 shows the efficiency of extraction of various metals byacid-amide in the absence of buffer. As can be seen, efficiency isreduced as compared with FIG. 6 (with buffer).

Example 8

Single crystals of some metal/acid-amide complexes (Sm, Eu, Lu) weregrown and analysed using X-ray crystallography. Results indicate thatthe intermediate Lanthanides (Sm, Eu) prefer to form a neutral dimerstructure of 2 acid-amide molecules binding 2 metal ions (see FIG. 8which shows an acid-amide/Ln (III) complex, wherein Ln=Sm or Eu). Thecomplex is a dimer in the solid state. The acid-amide takes up the coneconformation. The Sm cations are 8 coordinate, being bound to thedeprotonated phenolic oxygen atoms, the ethereal oxygen atoms, the amideoxygen and one of the carboxyl oxygens. The remaining two coordinationsites are made up from a methanol oxygen and a carboxyl oxygen from thesecond calixarene hence forming a bridge between the two calixarenes.

Molecular modelling suggested that all the larger Lanthanides would formisomorphic structures and that only the smaller Lanthanides (Gd-Lu)would form discrete monomeric complexes. Lu (smallest Lanthanide) formsa structure with 1 acid-amide and 1 metal ion which requires a counteranion for charge neutrality. FIG. 9 shows an acid-amide/Lu (III) complexwith NO₃ as the counter ion. The Lu cation is shown to be sevencoordinate, bound to the two phenolate oxygens, the two etherealoxygens, the amide oxygen, one carboxylate oxygen and a water molecule.

These structures may help to account for the specificity demonstrated inExamples 5 and 6.

Example 9

Metal/acid-amide complexes were further investigated by extracting thecomplexes from the hydrophobic phase and determining themetal:acid-amide ratio. For La, Lu and U at pH 6 the M:L ratio was 1:1.This confirms the solid-state ratios determined for the largerlanthanides and Lu by X-ray crystallography in Example 8 (which were 2:2and 1:1 respectively). No X-ray data was obtained for U.

Example 10

Acid-amide dimers and esters thereof were prepared based on theacid-amide calixarenes of the present invention, as described in moredetail in Example 15 below. Some of these are shown FIGS. 10 to 14.

Compound 13b (FIG. 10) was prepared in order to mimic thecalixarene/Lanthanide complex of FIG. 8. The dimer did not complex La³⁺at pH 6, a more alkaline pH (i.e. pH 9) being required to quantitativelyextract La. This is possibly because steric hindrance may reduce La'sability to compete with protons for oxygen coordination sites at lowpHs. Metal:Ligand ratios in the solvent extracted complex weredetermined to be 0.54 i.e. for every 2 La:dimer. This suggests that allsix ionizable —OH groups are dissociated forming a complex similar tothat in FIG. 6. La, in the presence of Lu and U, at pH 9 ispreferentially extracted.

By contrast, U is quantitatively extracted at pH 6 (unlike La). Themetal:Ligand ratio at pH 6 was approximately 1:1 suggesting a differentcomplex is forming to that formed by La at higher pH.

Compound 11b (FIG. 11) was prepared in order to optimise the bridginggroup between the calixarenes for U extraction. The meta-di-phenylaminelinkage restricts the two calixarene halves such that the carboxylgroups are close to each other. This is the predicted conformation inthe metal complex, unlike the conformation in free solution, wherein itis predicted that steric effects will mean that the halves arediametrically opposed around the bridging group. The compound extractedU much more efficiently at pH 9 than pH 6 (80% rather than 20%). This isin contrast to Compound 13b above. The more alkaline operatingconditions of 11b may be more applicable to some clean up applications.

In Compound 10 (FIG. 12) the carboxy group of the calixarenes has beenprotected with benzyl alcohol. No U extraction occurred at pH 6 (as withCompound 13b). Compound 11 (FIG. 13) is similar to compound 10 but wasgenerated using a different diamine. Again no extraction of U occurredat pH 6. Significant extraction of U and Hg occurred at pH 9notwithstanding the presence of the protecting group. This implies thata deprotonated carboxy group is not necessary for completing U or Hg,but that the phenolic groups (deprotonated at high pH) are crucial toextraction. Compound 11a is protected with as an ethyl ester, and hasthe di-phenylamine linkage of compound 13b. Again no U extractionoccurred at pH 6.

It is clear that the pH dependent specificity of the dimeric compoundsabove give them utility in the selective extraction of different metals.

Example 11

The acid-amide was physisorbed and immobilised onto polystyrene divinylbenzene beads in an inert diluent. Solutions containing U were passedthrough a chromatography column containing the beads at variousdifferent pHs at a flow rate of approximately 2 mls/min. A controlexperiment was carried out with blank beads. The results are shown Table2. As can be seen, above pH 2 extraction of U occurred, reaching 100% atpH 3. The kinetics were fast enough to absorb the U from the relativelyfast moving mobile phase.

TABLE 2 Extraction Efficiency Acid-amide pH resin Blank 1 2 10 2 37 34 3100 20 4 100 21 6 93 21 9 34 0

Example 12

Synthesis of acid-amide (designated A954 below).

Synthetic Scheme

A954 was synthesised using the route shown in FIG. 15. The bis-ester(A955) was synthesised following the literature method of Collins et al(1991) J. Chem Soc., Perkin Trans.,1, 3137. Reaction ofp-tert-Butylcalix[4] arene with 2 equivalents of ethyl bromoacetate inacetone with potassium carbonate (as base) gave the bis-ester in goodyield. This was mono-deprotected using 1 equivalent of potassiumhydroxide in ethanol. Although the product contained traces of bothbis-ester and bis-acid as impurity, it was used without furtherpurification and the impurities removed in subsequent steps. Overnightreflux with thionyl chloride in dichloromethane gave the acyl chloridewhich was reacted immediately with excess diethylamine (indichloromethane with triethylamine present) to give the calixareneamide-ester (A953) in 72% overall yield. Finally, deprotection of theester group using potassium hydroxide in ethanol gave the desiredacid-amide (A954).

Detailed Synthesis

NMR data was compiled after each step, but is shown only for the finalproduct.

A955: p-tert-Butylcalix[4] arene 10 g, 0.015 mol) and anhydrouspotassium carbonate (4.68 g, 0.34 mol) were slurried in dry acetone(distilled from CaSO₄) for 2 hours. Ethylbromoacetate (5.15 g, 0.031mol) was added. and the mixture stirred under nitrogen for three days.It was then filtered, the solvent distilled off and the residue driedunder vacuum. It was then slurried with cold ethanol to form a whitepowder and collected by filtration. This solid was washed with a furtherquantity of cold ethanol and dried under vacuum. Yield 8.97 g (73%).

951: bis-ester A955 (8.0 g, 9.76 mmol) was slurried in ethanol (600 ml).Potassium hydroxide (85% AR, 0.55 g, 9.76 mmol) added and the mixtureheated to reflux for 1-2 hours. On cooling the ethanol was reduced involume (to 50-100 ml) and 1 M HCl added to precipitate the product. Thiswas collected by filtration and washed with water(50 ml). The productwas dried under vacuum.

Yield 6.95 g (90%) (Found: C, 73.84; H, 7.42; required C, 75.72; H.7.62%);

A953: acid-ester 951 (5.0 g, 6.31 mmol) was refluxed overnight withthionyl chloride (3.5 ml) in dry dichloromethane (100 ml). The solventwas then removed by distillation and the oily yellow residue dried undervacuum. Additions of dichloromethane (4-5 ml) were necessary to helpazeotrope off the last traces of thionyl chloride. When dry, the productwas a glassy off-white solid. The acyl chloride ester was then dissolvedin dry dichloromethane (50 ml). To this solution was added dropwise, asolution containing dry diethylamine (dried over KOH) (0.98 ml, 9.45mmol) and dry diethylamine (dried over CaH₂) (0.87 ml, 6.31 mmol) in drydichloromethane (50 ml) over 30 minutes. After stirring overnight atroom temperature, the solution was transferred to a dropping funnel andwashed with 1 M HCl (50 ml) and then water (50 ml). It was then driedover MgSO4, filtered and the solvent removed in vacuo. The crude productwas purified by column chromatography on silica (Kieselgehl) usingdichloromethane/methanol (98:2) eluent.

Yield 3.86 g (72%) (Found: C, 74.83; H, 8.13; N, 2.12. required C,74.87,H, 8.72, N, 1.61%)

954: amide-ester, A953, (2.20 g, 2.48 mmol) was dissolved in ethanol(150ml) and potassium hydroxide (0.28 g, 4.96 mmol) added. The resultingsolution was then refluxed for 2 hours. After cooling to roomtemperature, the volume of the solution was reduced to ca. 25 ml byrotary evaporation. Addition of 1 M HCl gave a white precipitate whichwas collected by filtration and washed with water. It was then dissolvedin dichloromethane (30 ml. washed with 1 M HCl (30 ml) water (30 ml) andthen dried over MgSO4. The solvent was removed in vacuo to give a foamywhite solid. It was converted to a powder by dissolving in a minimum ofdichloromethane and adding hexane (30-40 ml)—evaporation to dryness gavea white solid. Yield 2.06 g (97%) (Found: C, 75.24; H, 8.77; N, 1.97.required C, 75.33, H,8.51, N, 1.69%).

NMR data (300 MHz, CDCl3) 1.07 (9H, s, —Bu). 1.11 (9H, s, —Bu), 1.25(18H, s, —Bu), 1.25 (3H, t, —CH₃), 3.38 (2H, d, Ar—CH₂—Ar), 3.38 (2H, q,—NCH₂—), 3.42 (2H, d, J=13.0 Hz, Ar—CH₂—Ar), 3.55 (2H, q, —NCH₂—), 4.22(2H, d, J=13.0 Hz, Ar—CH₂—Ar), 4.30 (2H, d, J=13.3 Hz, Ar—CH₂—Ar). 4.64(2H, s, —OCH₂CO—), 4.78 (2H, s, —OCH₂CO—), 6.93 (2H, s, Ar), 6.99 (2H,s, Ar), 7.03 (2H, d, Ar), 7.06 (2H, d, Ar), 8.90 (2H, br s, —OH); (75.42MHz, CDCl3) 13.02, 14.36, 31.12, 31.68, 32.17, 32.35, 33.91, 34.05,34.16, 40.78, 41.20, 72.44, 73.29, 125.24, 125.55, 126.10, 127.21,128.29, 132.71, 132.94, 142.32, 147.49, 148.51, 149.76, 150.11, 150.21,166.71, 170.44; FAB m.s., m/z 864 (M+2Na⁺—H., 18%), 842 (M+Na⁺, 100),820 (M+, 10).

It should be noted that the synthesis of other calixarenes fallingwithin the claims of the present application may be readily achieved bythe skilled person in the light of the disclosure of the presentdocument, particularly in combination with the common general knowledgeof the skilled person, as evidenced for example by the teaching andreferences of EP 0 432 989.

954/Metal Complex Synthesis

To prepare Ln (NO₃)₃.nDMSO, n=3,4 Ln₂O₅ was dissolved in a minimum ofnitric acid (fast exothermic process for large Ln, slow process forsmall Ln). To the resulting solution was added a 5-6 fold excess ofdimethyl sulphoxide. Ethanol and then diethyl ether were then added toprecipitate the product. Occasionally, when the product oiled out, itwas necessary to decant the mother liquor, add more ethanol/diethylether and then scratch with a glass rod. The product was then collectedby filtration, redissolved in DMSO and precipitated with ethanol/ether.The final product was collected by filtration and dried under vacuum.All DMSO solvates gave elemental analyses in accordance with theirproposed structures.

A simpler method involved the use of Ln (NO₃)₃ penta and hexahydratesinstead of the oxide. In this case the salt was twice dissolved in DMSOand precipitated with ethanol and diethyl ether.

The calixarene acid-amide A954 (0.0189 g, 0.023 mmol) was dissolved in 1ml DMF. To this solution was added Ln (NO₃)₃.nDMSO (n=3 or 4, 0.025mmol) also in 1 ml DMF. After the further addition of 30 microlitres oftriethylamine (excess), the solution was immediately filtered and leftto stand. As mentioned earlier, the larger lanthanides precipitatedquite quickly from solution whereas the smaller ones took considerablylonger. The precipitated complex was then collected by filtration andwashed with a minimum of cold ethanol (ca. 0.5 ml) and dried undervacuum. Attempts were made to recrystallise these complexes fromdichloromethane/ethanol. This typically involved dissolving the complexin dichloromethane (1.5 ml) and then adding ethanol (1 ml). Afterfiltering, the solution was left to slowly evaporate.

For the larger lanthanides (La-Eu), the complex precipitated fairlyquickly from solution, and was then recrystallised fromdichloromethane/ethanol. In case of the Eu and Sm complexes, crystalssuitable for X-ray crystallographic analysis were isolated.

Precipitated from DMF/NEt:Sm complex of A954; Found: C, 64.0; H, 7.2; N,3.3. required C, 64.3, H, 7.5, N, 3.7%.

Eu complex of A954; Found: C, 63.9; H, 7.1; N, 3.4. required C, 64.2, H,7.5, N, 3.7%.

Recrystallised from ethanol/dichloromethane:

Eu complex of A954; Found: C, 65.6; H, 7.5; N, 2.8. required C, 65.6, H,7.9, N, 2.6%.

The smaller lanthanide complexes (Lu) less readily precipitated from DMFsolution than the larger ones described above, instead crystallising outonly after a period of weeks.

Example 13

Synthesis of azacrown-acid calix[4]arenes

In attempt to form discrete monomeric complexes across the Lanthanideseries, the azacrown-acid calix[4]arenes A957 and A959 (FIG. 16) wereprepared with the idea that the extra O-donor sites present would moreeasily satisfy the normal 8-10 coordination sphere of the largerLanthanides.

The synthetic scheme used in the synthesis of the simpler acid-amide(A954) was also applied in the synthesis of theazacrownacidcalix[4]arenes, FIG. 15. For the final deprotection step, inorder to eliminate the possibility of isolating alkali-metal complexesof the product, potassium hydroxide was used as base in the deprotectionof the N-aza-15-crown-5 ligand and sodium hydroxide in the case oftheN-aza-18-crown-6 ligand.

Isolation of Complexes

Preliminary work was also begun on the isolation of the Lanthanidecomplexes of these ligands, the majority of this involvingtheN-aza-15-crown-5 analogue only. The same methods were applied as forthe simpler acid-amide (A954) and, in general, the same observationsmade. Again the larger Ln cations formed complexes which readilyprecipitated from DMF solution. Attempts at recrystallisation of thesecomplexes from dichloromethane/ethanol again yielded X-raycrystallographic quality crystals of the Sm complex. Disappointingly,however, the anticipated monomeric complex was not formed. Instead, asimilar dimeric structure was adopted with the aza-crown folding awayand not coordinating to Sm.

Example 14

U.V. Spectra

The observed maxima for the 954 acid-amide are listed in Table 3together with the corresponding values for selected complexes. Theextinction values given are approximate only. Given that the samplesizes measured were only about 1 mg, weighing errors could easilyaccount for apparent differences in absorption between related species.

Example 15

Synthesis of acid-amide dimer. The dimers of Example 10 were prepared bymethods analogous to those above. In the case of 11a, compound A952(FIG. 15) was prepared as described above. Two molecules of A952 weredimerised with m-phenylenediamine in dichloromethane and triethylamine.The yield was 68%. Compound 11b was prepared from 11a by regeneratingthe carboxy group with potassium hydroxide in ethanol. The yield was90%. The other dimers were prepared using different diamines (e.g.1,2-di-(methylamino)ethane for 11 and 13b). Other protecting groups canbe added either as alcohols to the deprotected acid group, orincorporated into the precursor e.g. by substituting theethylbromoacetate used to prepare A955 in Example 12 with a bromylatedbenzyl ester. The diamine synthetic route is flexible in that a widevariety of spacer groups may be introduced between the calixarenehalves, allowing factors such as chain length, coordination etc. to beassessed.

TABLE 3 Wavelength Maxima Compound/complex (nm) cm⁻¹M⁻¹ 954 228 36000282 9500 954/La 228 50000 260 (sh) 15000 307 9400 954/Sm 228 46000 260(sh) 13000 307 9600 954/Eu 228 48000 260 (sh) 15000 306 9700

Example 16

synthesis of the ester-thioamide A960 A960 was synthesised using theroute shown in FIG. 17. The precursor A953 was prepared by the routeshown in FIG. 15 and Example 12. Lawesson's reagent (0.49 g, 1.2 mmol)was added to a solution of ester-amide A953 (1.0 g, 1.17 mmol) intoluene (20 cm³) and the mixture was heated at 80° C. for 4 hr. Aftercooling to room temperature, the toluene was removed under reducedpressure to give a yellow oil. This oil was dissolved in acetonitrile(15 cm³) and filtered through an alumina pad. Dropwise addition of waterto the filtrate afforded a yellow precipitate, which was removed byfiltration and recrystallised from dichloromethane-ethanol to affordA960 as yellow prismatic crystals (095 g, 94%). The structure of thiscompound was confirmed by NMR, mass spectrometry and X-raycrystallography.

Example 17

synthesis of the acid-thioamide A961 A961 was synthesised using theroute shown in FIG. 17. The ester-thioamide A960 was synthesised by theroute shown in FIG. 17 and Example 16. Potassium hydroxide (0.036 g,0.65 mmol) was added to a solution of ester-thioamide A960 (0.5 g, 0.58mmol) in ethanol (25 cm³) and the solution heated under reflux for 2 hr.The ethanol was reduced in volume to approximately 5 cm³ and 1 M HCladded to precipitate A961 as a pale yellow powder which wasrecrystallised from dichloromethane-hexane (0.41 g, 85%). The structureof this compound was confirmed by NMR and mass spectrometry.

Example 18

FIG. 18 shows the ability of the calixarenes A954, A960 and A961 toextract cadmium ions at pH 9.4. Equal volumes of aqueous cadmium cyanidesolution (pH 9.4, [Cd²⁺]=0.238 mMolar) and a solution of a calixarene indichloromethane were mixed for 15 minutes by stirring. The aqueous andorganic phases were then allowed to separate for about 30 minutes. Theaqueous layer (Aq1) was then removed, and the organic layer was washedwith a nitric acid blank (pH 9.4). The aqueous and organic layers wereallowed to separate for about 30 minutes, and the aqueous layer was thenremoved (Aq2). Aq1 contained the cadmium ions that had not beenextracted by the calixarenes, whereas Aq2 contained the cadmium ionsthat had been extracted by the calixarenes (and subsequently liberatedby acidification of the organic layer). Aq1 and Aq2 were made up toknown volumes. ICP AES (inductively coupled plasma atomic emissionspectroscopy) was then used to determine the concentration of cadmiumions in the solutions. These figures can readily be used to determinethe percentage extraction of cadmium for a given ratio of concentrationof calixarene:cadmium.

FIG. 18 indicates that both the acid-thioamide A961 and theester-thioamide A960 are capable of extracting cadmium ions fromsolution. The order of efficiency of extraction is acid-thioamide,A961>acid-amide, A954>ester-thioamide, A960. The order can be explainedby the fact that both A961 and A954 have a proton that can be readilylost from the acid substituent. The resulting anion will attract andretain cadmium ions more effectively than the (usually uncharged) estergroup The acid-thioamide (A961) forms complexes with cadmium morereadily than the acid-amide (A954) because the S atom in A961 is a“softer” atom than the 0 atom in A954, and is thus more polarisable andthus is more likely to form a complex with a Cd²⁺ ion, which is itself a“soft” ion.

What is claimed is:
 1. A calixarene dimer comprising a calixarene offormula (I)

wherein: L is [—CH₂—] or [—O—CH₂—O—] and is the same or differentbetween each aryl group; R⁵ is H, halogen, or is a C₁-C₁₀ aliphatichydrocarbyl group, C₆-C₂₀ aryl group or a C₆-C₂₀ hydrocarbylaryl group,any of which is optionally substituted by one or more halo or oxo groupsor is interrupted by one or more oxo groups, and R⁵ is the same ordifferent on each aryl group; R¹ is a carboxy group which is or is notprotonated or protected; two groups out of R², R³ and R⁴ are H; and theone group out of R², R³ and R⁴ which is not H is an amide group offormula (II)

wherein n is 1, 2 or 3 and R⁶ and R⁷ are H, halogen or a C₁-C₁₀aliphatic hydrocarbyl group, and are the same or different on eachcarbon, and wherein R⁸ and R⁹, which is the same or different, are H ora C₁-C₁₀ aliphatic hydrocarbyl group which is substituted by one or morehalo groups, or is a cycloaliphatic ring formed by R⁸ and R⁹ togetherwherein one of the R⁸ and R⁹ groups is conjugated to a secondcalixarene.
 2. The dimer as claimed in claim 1 comprising twocalixarenes of formula (I) wherein the R⁸ or R⁹ group of one calixareneis conjugated to the R⁸ or R⁹ group of the other calixarene, optionallythrough a spacer group R¹¹, the optional spacer R¹¹ being a C₁-C₆aliphatic hydrocarbyl group, or a C₆-C₁₀ aryl group, or a C₆-C₁₆hydrocarbylaryl group any of which is optionally substituted by one ormore halo or oxo groups or is interrupted by one or more oxo groups. 3.The dimer as claimed in claim 2 wherein there is a 1, 2, 3 or 4 atomchain between the nitrogen atoms of the two amide groups.
 4. The processfor preparing a dimer as claimed in claim 2 comprising reacting twoequivalents of a calixarene bearing an acyl chloride substituent with 1equivalent of diamine.
 5. A method of sequestering metals comprisingcontacting metals with a calixarene dimer as claimed in claim
 2. 6. Themethod as claimed in claim 5 wherein the method is carried out at a pHof between 2 and
 11. 7. The method as claimed in claim 5 wherein the pHat which the method is carried out is buffered.
 8. A method ofsequestering metals comprising the steps of: (i) dissolving a calixarenedimer of claim 1 in an hydrophobic organic solvent; (ii) mixing theorganic solvent with an aqueous phase containing metal ions; (iii)agitating the organic solvent and aqueous phase together; and (iv)recovering the metal from the organic phase.
 9. The method as claimed inclaim 5 or 8 wherein the metal is selected from a Lanthanide, U, Hg, Am,Pb, Sr, Bi and Y.